Klebsiella pneumoniae is a WHO priority pathogen, and contributes significantly to the mortality rate attributable and associated with antimicrobial resistant (AMR) pathogens. In clinical settings, K. pneumoniae causes cases of hospital- and ventilator-acquired bacterial pneumonia, and is a frequent co-morbidity of other lung diseases including bronchiectasis, cystic fibrosis, cancer and exacerbations of COPD. In the absence of a vaccine, there is the potential for K. pneumoniae to become untreatable, as resistance is now reported to every class of antibiotics, including last line agents such as carbapenems. Carbapenem resistance in K. pneumoniae is complex and multifactorial, but is most frequently mediated by the horizontal acquisition of any of several classes of carbapenemases, including the KPC, IMP, NDM, and OXA beta-lactamases.
This study investigated whether an ionophore compound, PBT2, would be effective in reducing carbapenem resistance in K. pneumoniae. PBT2 is a safe-for-human-use therapeutic, originally trialled for Alzheimer’s disease, that has subsequently proven to restore the efficacy of antibiotics against multi-drug resistant bacterial pathogens. Notably, PBT2 is able to break polymyxin resistance in MDR K. pneumoniae in sepsis models, and ampicillin resistance in S. pneumoniae in pneumonia infection models. Here we show that PBT2 can effectively reduce resistance to imipenem and meropenem in a panel of clinical isolates containing representatives from each of the major classes of carbapenemases. Increased susceptibility is associated with changes in intrinsic cellular processes, including dysregulation of zinc homeostasis and membrane permeability. These data suggest that PBT2 resensitises MDR K. pneumoniae to carbapenems by facilitating increased cellular uptake. This has implications for the potential use of PBT2 as a therapeutic agent against a broad range of pathogens as a permeabilisation agent for antimicrobials.